Diazine derivatives



the production of new and Patented Mar. 2, 1943 Gaetano F.

General Electric Company,

New York DAlelio, Pittsfield, Masa,

assignor a corporation of- No Drawing. Application November 1, 1941,

Serial No. 417,503

14 Claims.

This invention relates to new chemical compounds and more particularly to d'iazine' derivatives. The invention especially is concerned with useful pyrimidyl sulfamyl-carbocyclic-carbamyl-alkyl pyrimidyl sulfamyl carbocyclic thiocarbamyL alkyl sulfides.

The diazine derivatives of this invention may be represented graphically by the following gen- ,Inthe above'formula'n represents an integer and is at least 1 and noiignore than 2, Z represents a member of the class\ consisting of oxy en and sulfur, Y represents adivalent carbocyclic radical, and R represents a member of the class consisting of hydrogen and monovalent hydrocarbon and substituted hydrocarbon radicals, more particularly halo-hydrocarbon radicals. Since n represents an integer which is 1 or 2, it will be seen that the linkage of the suliamyl-carbocycliccarbamyl-alkyl or sulfamyl-carbocyclic-thiocarbamyl-alkyl grouping to the sulfur atom in all cases will be alpha or beta to the sulfamylcarbocyclic-carbamyl or thiooarbamyl grouping. It also will be observed that linkage of the pyrimidyl grouping to the sulfur atom is through a carbon atom.

Illustrative examples of radicals which- R'in theabove formula may represent are: aliphatic (e..g., methyl, ethyl, propyl, isopropyl, allyl, butyl, secsulfides and ondary butyl, isobutyl, butenyl, amyl, isoamyl,

hexyl, etc.), including cycloaliphatic (e. g., cy-

clopentyl, 'cyclopentenyl, cyclohexyl, cyclohexenyl,

cycloheptyl, etc.) aryl (e. g., phenyl, diphenyl or xenyl, naphthyl, etc.); (e. g., tolyl, xylyl, ethylphenyl propylphenyl, isopropylphenyl, allylphenyl, Z-butenylpheny'i, tertiary-butyiphenyl', etc): aryl-substituted ali-' phatic (e. g., benzyl, phenylethyl, phenylisopropyl, cinnamyl, etc.) and their homologues, as well as those groups with one or more-of their hydrogen atoms substituted by, for example, a halogen. Specific examples of halogeno-substituted hydroi carbon radicals are chloromethyl, chloroethyl, chlorophenyl, dichlorophenyl', chlorocyclohexyl, ethyl chlorophenyl, phenyl chloroethyl hromo- R in Formula I is hydrogen. However, there also may be produced in accordance with the present aliphatic-substituted aryl ethyl, bromopropyl, bromotolyl, etc. Preferably phenoxyphenylene;

' ticular utility in invention chemical compounds such. for instance, as those represented by the general formulas:

and

where 12, Z, Y and R have the meanings above given with reference to Formula I.

Illustrative examples ,of divalent carbocyclic radicals which Y in Formulas I, II and III may represent are: arylene, e. g., phenylene, xenylene, naphthylene, etc.'; alkarylene, e. g., Lbtolylene, para-(2,3-xylylene), etc.; cycloalkylene, e. g., cyclopentylene, cyclohexylene, etc.; cycloalkenylene, e. g., cyclopentenylene', cyclohexenylene, etc.;v I

-aminophenylene, acetophenylene, acetoxyphenyl ene, carbomethoxyphenylene, ethoxyphenylene,

hydroxyphenylene, methylphenylene (tolylene), allylphenylene, etc. Preferably Y is phenylene or methylphenylene.

The new compounds of this invention may be used as chemotherapeutic agents and as inter mediates in the preparation of derivatives thereof such as ureido, hydrazino, a-cyl, carbamyl, amidine, etc., derivatives of the individual pyrimidyi sulfamyl-carbpcyclic-carbamyl' (or thiocarbaing polymeric aldehydes and aldehyde-addition condensation products of parthe plastics and coating arts. Such condensation products are more fully described and are specifically claimed in my copending application Serial No. 117,505, filed conproducts, to yield These new organic sulfides currently herewith and assigned to the same assignee as the present invention. These new organic sulfides also may be compounded with rub-- tween a diamino [(-NHR)2] mercapto pyrimidine and a sulfamyl-carbocyclic-carbamyl (or thiocarbamyD-alkyl halide in the presence of a hydrohalide acceptor. Illustrative examples i mercapto pyrimidines that may beused, depending upon the particular sulfide desired, are:

2-mercapto 4,6-diamino pyrimidine 2-mercapto 4-bromotoluido fi-benzylamino pyrimidine Z-mercapto 4-phenylchloroethylamino G-phenethylamino pyrimidine z-mercapto 4-chloroani1ino S-ethylphenylamino pyrimidine Z-mercapto 4 cycloheptylamino 6 isopropylphenylamino pyrimidine 2-mercapto 4,6-diamino -methyl pyrimidine Z-mercapto 4,6-di-(methylamino) pyrimidine 2-mercapto 4,6-di-(methy1amino) 5-methyl pyrimidine 2-mercapto 4-chloroethylamino G-methylamino pyrimidine.

2-mercapto 4,6-di-(anilino) pyrimidine 2-mercapto 4,6-di-(anilino) 5-buty1 pyrimidine Z-mercapto 4-xenylamino 5-cyc1openty1 fi-amylamino pyrimidine 2-toluido 4-mercapto fi-cyclohexenyl 6-amino pyrimidine (2-toluido 4-amino fi-cyclohex'enyl '6-mercapto pyrimidine) z-mercapto 4-amino G-ethyIamino pyrimidine 2-mercapto 4,6-di-(propylamino) pyrimidine 2-a1lylamino 4-mercapto S-phenyl G-amino pyrimidine 2-isoamylamino 4-mercapto fi-chlorophenylamino pyrimidine 2-dichloroanilino ll-mercapto 5-tolyl 6-propylamino pyrimidine 2-cycloheptylamino 4-mercapto 6-isobutylamino pyrimidine 2-mercapto 4-allylamino 6-butylamino pyrimidine Z-mercapto 4-isobutylamino 6-cyclopentylamino pyrimidine 2-mercapto 4-(3'-butenylamino) 6-isopropylamino pyrimidine 2 mercapto 4-amino 6-chloroxeny1amino pyrimidine 2-mercapto 4-ethylphenylamino 5-naphthy1 6- xylidino pyrimidine -2-mercapto -isopropylanilino 5-benzyl 6-benzylamino pyrimidine 2-mercapto 4-phenethylamino 5- (2'-butenyl) 6- cyclopentenylamino pyrimidine 2-mercapto 4,6-diamino 5-bromotoly1 pyrimidine 2-mercapto -amino S-phenylisopropyl 6-chlorocyclohexylamino pyrimidine 2-mercapto 4-isobuty1amino 6-bromonaphthylamino pyrimidine 2-mercapto 4,6-diamino 5-phenylpropyl pyrimidine Z-mercapto 4-chl0r0benzylamino 5-chlorobutyl fi-bromoethylamino pyrimidine 2-mercapto 4-amino 5-ethylchlorophenyl 6-sec.

butylamino pyrimidine 2-mercapto 4-pentylamino G-cyclohexylamino pyrimidine 2-mercapto 4-n-hexylamino fi-xenylamino pyrimidine 2-mercapto 4-cyclohexenylamino B-naphthylamino pyrimidine Z-mercapto 4-amino fi-bromoethylamino pyrimidine Z-mercapto 4-amino G-methylamino pyrimidine 2-mercapto 4-aminoanilino 6-ethylphenylamino pyrimidine 2-mercapto 4-amino G-benzylamino pyrimidine 2-mercapto '4-chlorocyclopentylamino fi-toluido pyrimidine Illustrative examples of sulfamyl-carbocycliccarbamyl-alkyl halides and sulfamyl-carbocyclicthiocarbamyl-alkyl halides that may be employed, depending upon the particular endproduct sought, are;

Para (sulfonyl cyclohexylamide) phenyl (cyclopentyl) -thiocarbamyl chloro methane Para-(sulfonyl phenylamide) phenyl (chloroethyD-carbamyl bromo methane 4 (sulfonyl chlorotolylamide) cyclohexyl (phenyl) -carbamyl chloro methane 3 sulfamyl cyclopentyl carbamyl tolyl chloro methane Alpha [para (sulfonyl propylphenylamide) phenyl (bromophenyl) thiocarbamyl] betachloro ethane Alpha- [para- (sulfonyl phenylchloroethylamide) phenyl-(xenyl) carbamyl] alpha chlorotolyl beta-chloro ethane Ortho-(sulfonyl chloroethylamide) -pheny1-carbamyl chloro methane Meta (sulfonyl naphthylamide) phenyl car bamyl iodo methane Para-sulfamyl-phenyl-carbamyl alpha (bromophenyl) beta-chloro ethane Para (sulfonyl isobutylphenylamide) phenyl carbamyl naphthyl chloro methane Various hydrohalide acceptors may be employed. I prefer to use a hydrohalide acceptor that will react with the mercapto pyrimidine to form a water-soluble salt. Examples of such acceptors are the alkali-metal hydroxides, e. g., sodium hydroxide, potassium hydroxide, etc. Additional examples of hydrohalide acceptors that may be used are other inorganic bases, e. g., calcium hydroxide, barium hydroxide, ammonium hydroxide, etc.; carbonates of inorganic bases, including the carbonates of alkali-metals; organic amines such as tertiary amines, e. g., trimethyl amine, triethyl amine, tributyl amine, pyr-- idine, dimethyl aniline, quinoline, etc.; quaternary ammonium bases, e. g., tetramethyl ammonium hydroxide, etc.; and the like.

The reaction between the mercapto diamino 2,312,091 3 pyrimidine and the sulfamyl -carbocy li Z-lsoamylamino ri-chloro fi-chlorophenylamino bamyl (or thiocarbamyl) -alkyl' halide may be yrimidine r d out in n a e m n r, but prefe 2-chloro 4-amylamino 6-cyclohexylamino pyrimably is eflected in the presence of a suitable soiidine vent-or mixture of solvents. Although various 5 2-ch1oro 4-n-hexylamino 6-xenylamino pyrimisolvents and solvent mixtures maybe employed, dine for economic reasons and because of their emi- 2-bromo 4-cyclohexenylamino 5-chlorocyclohexnent suitability I prefer to use water or a mixenyl B-naphthylamino pyrimidine ture of water and alcohol. The reaction may be 2-chloro 4-chlorocyclopentylamino 6-toluido pycarried out under a variety or temperature and rimdine pressure conditions, for-instance at normal or z-dichloroanilino 4-chloro -toly16-propylamino at elevated temperatures and at atmospheric, pyrimidine sub-atmospheric or super-atmospheric pressures. z-cycloheptylamino 4-bromo 5-isobutylamino py- However, normal pressures are preferred for rimidine convenience. 2-chloro 4-amino 6-chloroxenylamino pyrimidine I The above reaction may be represented by the z-chloro 4-ethyiphenylamino 5-naphthyl 6-xylifollowing general equation: dino pyrimidine (BEN)?- halide acceptor L N -In the above equation X represents halogen, 2-'-ch1oro -isopropylanilino 5-benzyl6-benzylamiand 11., Z, Y and R have the same meanings as no pyrimidine given above with reference to Formula I. 2-bromo 4-phenethylamino 5-(2'-'butenyl) 6-cy- The newchemical compounds of this invention cylopentenylamino pyrimidine also may be prepared by effecting reaction be- 5 Z-chloro 4,6-diamino 5-bromotoly1 pyrimidine tween a halogenated diamino pyrimidine and a 2-bromo 4-amino 5-phenylisopropyl fi-chlorocysulfamyl-carbocyclic-carbamyl or -thiocarbamy1 clohexylamino pyrimidine. mercapto alkane in the presence of a hydrohalide Z-ch-loro 4-bromonaphthylamino fi-isobutyiamino acceptor. This reaction may be carried out by pyrimidine any suitablemeans but preferably is effected in 2-chloro 4,6-diamino 5-phenylpropyl pyrimidine the presence of an anhydrous solvent.- An an-- 2-chloro 4-bromoethylamino 5-ch1orobutyl '6- hydrous solvent, e. g., alcohol, is desirable bechlorobenzylamino pyrimidine cause one of the reactants, namely, the. halo- 2-chloro 4-amlno 5-chloroethylpheny1 6-sec.- genated pyrimidine, is hydrolyzable. The other butylamino pyrimidine conditions of reaction may be the same as de- 2-iodo 4-amino fi-bromoethylamino pyrimidine scribed above with reference to the first-men- Z-bromo 4-dichloroanillno G-chloroethylamino ti'oned method of preparation. pyrimidine Illustrative examples of halogenated diamino 2-chloro 4-bromotoluldo G-benzylamino pyrimipyrimidines that may be used, depending on the dineend-product desired, are: 2 -ch1oro 4-aminoanilino G-ethylamino pyrimidine 2-chloro 4-phenylchloroethylamino G-phenethyl- 2-chloro 4,6-diamino pyrimidine amino pyrimidine 2-chloro 4,6-di-(methylamin0) pyrimidine 2-chloro 4-chlorocycloheptylamino 6-isopropy1- 2-chloro 4,6-di-(anilino) pyrimidine amino pyrimidine i Z-bromo 4-amino G-ethylamino pyrimidine 2-ch1oro 4-isopropylanilino 6-phenylpropylamlno 2-chloro 4,6-di-(propylamino) pyrimidine pyrimidine 2-chloro 4-methylamino fi-chloroethylamino py- 2-bromo 4,6-di-(methylamino) 5-methyl pyrimidine I Illustrative examples of sulfamyl-carbocycliccarbamyl or thiocarbamyl'mercapto alkanes that may be used, depending upon the particular endrimidine 2-i0do 4,6-di-(anilino) fi-butyl pyrimidine pmdu-ct m 2-bromo 4-al1ylamino fi-butylamino pyrimidine Pflra-sulfamylWhenybcarbamyl 1 7 1 1 h- 2-chloro 4-isobutylamino G-cyclopentylamino pyane 1 rimidine v I Alpha-(para-sulfamyl phenyl carbamyl) beta- 2-chloro 4-(3-butenylamino) G-isopropylamin'o e ap o etha e v I pyrimidine Alpha-(meta-sulfamyl-phenyl-carbamyl) alpha- 2-chloro 4-amylamino 6-cyclohexylamino pyrimimercapio ethane dine v Alpha [para- (sulfonyl methylamide) -phenyl- 2-chloro 4-amylamino 5-cyclopentyl fi-xenylamithlocarbamyl] alpha-memento Dentane no pyrimidine 7o Ortho-sulfamyl-phenyl-(methyl)-carbamyl mer- 2-toluido 4-bromo 5-cyc1ohexenyl G-amlno pybapto methane rimidine (2-to1uido i-amino 5-cyclohexenyl 6- h w fl ap hyl-l-carhamrl) betabromo pyrimidine) mercapto i-l butene 2-allylamino 4- chloro 5-phenyl fi amino pyrimi- Alpha-(para-sulfamyl-chlorophenyl.- carbamyl) dine. alpha-ethyl beta-phenyl beta-mercapto ethane Para-(sulfonyl pentylamide)-tolyl-carbamyl cypyrimidine was then added and until clopentyl mercapto methane clear solution resulted. A second solution was Para-(sulfonyl 3-butenylamide)-chlorotoly1-(buprepared by dissolving 200 parts para-(chlorotyl) -carbamy1 mercapto methane acetamido) benzene sultonamide in 3500 parts of Para-(sulfonyl cyclohexylamide) -phenyl-(cycloan aqueous alcohol solution containing 750 parts pentyl) -thiocarbamyl mercapto methane Para-(sulfonyl phenylamide) phenyl (chloroand then mixed. The resulting homogeneous ethyl) -carbamyl mercapto methane, solution was allowed to stand for one hour while 4-(sulfony1 chlorotolylamide) -cyclohexyl-(phencoolin r after it was ated on a team yl) -carbamyl mercapto methane Plate. A voluminous precipitate formed. The re- Alpha [para (sulfonyl propylphenylamide) action mass was cooled at about 40 to 45 F. for

phenyl (bromophenyl) thiocarbamyl] betaabout 16 hours and then filtered. The residue mercapto ethane Alpha- [para-(sulfonyl phenylchloroethylamide) amyl P yl Carbflmyl hyl Sulfide was phenyl (xenyl) carbamyl] alpha-chlorotolyl 1.3 washed free of water-soluble salts and then dried beta-mercapto ethane at 70 C. The yield of dried product was 87.5%.

Meta (sulfonyl naphthylamide) phenyl car- Its m ltin paint was 2 to 2 0 C- A n t en bamyl mercapto methane determination showed that it contained 22.8%

Ortho- (sulfonyl chloroethylamide) -phenyl carnitrogen, which checks with the theoretical nitrobamyl mercapto methane 20 gen content of 4,6-diamino pyrimidyl para-sulf- Para-sulfamyl-phenyl carbamyl alpha- (bromoy -phenyl-c rba yly Sulfide Within the phenyl) beta-mercapto methane limits of experimental error.

Para (sulfonyl butylphenylamide) -phenyl-car- Example 2 bamyl naphthyl mercapto methane Alpha-[(sulfonyl isopropylamide)-cyclohexenyli mino pyrimldy1-4 para-sulfamyl-phen- (methyl)-carbamyl] alpha, beta-di-(phenyl) yl-carbamyl-methyl sulfide is produced in the alpha-methyl beta-chlorobutyl beta-mercapto Same manner as described er p e 1 With ethane the exception that 114 parts 4-mercapto 2,6-diamino pyrimidine is used instead of 114 parts 2- The hydrohalide acceptor may be the same as mercapto 4,6-diamino pyrimidine.

described above with reference to the first-named Example 3 method of preparing the compounds of this invention. ,6-diamino pyrimidyl-2 para-sulfamyl-phen- The general reaction for this alternative ba yy fi e iS p p in method.of preparing my new chemical sentially the same manner as set forth under pounds is illustrated by the following equation: E p e 1 with the exception that, instead of In the above equation X represents halogen, 60 bara-(chloroacetamido) benzene sulfonamide, an and n, Z, Y and R have the same meanings as equivalent amount of para-(chlorothioacetgiven above with reference to Formula I. fl fl) benzene SulfOIlamide is employed.

In order that those skilled in the art better may understand how the present invention may Example 4 be carried into effect, the following specific T mp re v n. Al p r re y wei ht. 4,6-diamino pyrimidyl-Z para-sulfamyl-tolyl- Example 1 carbamyl-methyl sulfide is prepared in essentially the same manner as described under Example 1 with the exception that an equivalent amount of para-(chloroacetamido) toluene sulfonamide is used instead of para-(chloroacet- Z l ,-NRYSO2NHR salt of hydrohalide acceptor This example illustrates the preparation of 4,6- diamino pyrimidyl-2 para-sulfamyl-phenyl-carbamylmethyl sulfide, the formula for which is:

f z amido) benzene sulfonamide. C Other examples 'of' the new chemical com- 0 pounds of this invention are shown below: {MN-(L! 3 s-om-ti-maGsomm N vn NH:

Parts 2-mercapto 4,6-diamino pyrimidine 114 Para (chloroacetamido) benzene sulfonl amide 200 Haw-0 CS-CHQCHCNHOSO;NH, Sodium hydroxide 34 The sodium hydroxide was dissolved in 600 water. The two solutions were heated separately comprising 4,6-diamino pyrimidyl-Z para-sulsulfamyl-carbocyclic-carbamyl and -thiocarbamyl sulfur derivatives of the 1,3- or-metadiazlnes (pyrimidines), the corresponding derivatives of the 1,2- or ortho-diazines (pyridazines) and of the 1,ior para-diazines (pyrazines) may be prepared. It also will beunderstood by those skilled in the art from the foregoing description of the preparation of a diazine monosulfide N that similar compounds'may be prepared in which two or three sulfur atoms are attached directly to a carbon atom of the diazine nucleus, thus:

What I claim as new and desire to secure by Letters Patent of the United States is:

1. Chemical compounds corresponding to the general formula Y where n represents an integer and is at least 1 and not more than 2, Z represents a member of the class consisting of oxygen and sulfur, Y

v represents a divalent carbocyclic radical, and R represents a member of the class consisting of hydrogen and monovalent hydrocarbon and halohydrocarbon radicals.

2. Chemical compounds as in claim 1 wherein R represents hydrogen.

3. Chemical compounds as in claim 1 wherein R represents hydrogen, Z represents oxygen and n is 1.

4. Chemical compound corresponding to the general formula where n represents an integer and is at least 1 and not more than 2, Z represents a member of the class consisting of oxygen and sulfur, Y represents a divalent carbocyclic radical, and R represents a member of the class consisting of hydrogen and monovalent hydrocarbon and halohydrocarbon radicals.

5. Chemical compounds corresponding to the general formula where Y represents a divalentcarbocyclic radical, and R represents a member of the class consisting of hydrogen and monovalent hydrocarbon and halo-hydrocarbon radicals.

6. A diamino pyrimidyl sulfamyl-carbocyclic- V para-sulfamylwhere n represents an integer and is at least 1 r and not more than 2, Z represents a member of the class consisting of oxygen and sulfur, Y represents a divalent carbocyclic radical, and R represents a member of the class consisting oi! hydrogen and monovalent hydrocarbon and halohydrocarbon radicals, said method comprising effecting reaction, in the presence of a hydrohalide acceptor, between (1). a. mercapto pyrimidine corresponding to the general formula where R has the meaning above given, and (2) a halide corresponding to the general formula where X represents halogen, and 12., Z, Y and R have the meanings above given.

13. A method as in claim 12 wherein the hydrohalide acceptor is an alkali-metal hydroxide. 14. The method of preparing 4,6-diamino pyrimidyl 2 para sulfamyl phenyl-carbamylmethyl sulfide which comprises efiecting reaction, in the presence of a hydrohalide acceptor, between 2-mercapto 4,6-diamino pyrimidine and para- (chloroacetamido) benzene sulfonamide.

GAETANO F. DALELIO.

for that portion reading Certificate of Correction Patent No. 2,312,691. March 2, 1943.

' GAETANO F. DALELIO It is hereby certified that errors appear in the printed specification of the above numbered patent re uiring correction as follows: Page 1, second column, line 46, for. sulfiide read s fide; page 3, second column, lines 9-10, for pyrimdine read pyrimidine; page 4, second column, line ,20, for pyrimidyl read pyrimidyl-Z; page 5, first column, line 49, Formula XIII, strike out the parentheses before and after "para-sulfamyl-phenyl-carbamyl-methyl"; line 75, Formula XV, for falpha [(parasulfonyl read alpha-[(pam-sulfonyl; and second column, line 13, Formula XVII,

BIC!

' aN- I line 17, for 5-cyclophexenyl read 5-cyclohezrenyl; line 28, Formula XVIII, for

pagasulfamyb read para-suljamyb; lines 4142, Formula XX, for that portion rea ng HoCr-Q CIHO d CiHl SCHC-HN- s-dH-c- -NH page 6, line 47, Formula XXVII, for parasulfonyl read para-sulfonyl; and that the said Letters Patent should be read with these corrections therein that the same may conform to the record of the case in the Patent Ofiice.

Signed and sealed this 8th day of June, A. D. 1943.

HENRY VAN ARSDALE,

Acting Commissioner of Patents. 

